Comment by Donld F. Klein

Donald F. Klein’s comment on Edward Shorter’s Endocrine Psychiatry in Historical Perspective 

Ned Shorter produced his usual fact-packed review and trenchant observations.  His conclusion that endocrine psychiatry is on the back burner was protested by Brown and Winokur who pointed to numerous studies revealing the complexities of brain endocrine relationships.  However, my take was that these numerous, remarkable, exciting, biological facts were still tangential to the concerns of clinical psychiatry: mechanisms of disease, diagnosis, prognosis, therapeutics.

My introduction to the intricacies of “Endocrine Psychiatry” was in 1976, when Ed Sachar recruited me to go to Columbia with him as his inside man. Ed's early demise was an incalculable loss to psychiatric progress.

His pioneering work on the pulsatile release of cortisol and its relation to stressors has never been adequately studied. Enthused by him in our work producing panic by IV lactate challenges, specifically in panic disorder patients, we were stunned to find no evidence of HPA activation. When showed to Ed, he looked at me sadly and said, “What mistake could you have made?” However, his understandable skepticism quickly faded, and this sturdy finding remains a baffling puzzle.

Some, not that recent, endocrinological findings have direct psychiatric implications but have not received adequate notice.

The Columbia group has clearly shown that the non-melancholic, although substantially impaired, group of atypical depressives have no evidence of cortisol stimulation. (1)

The shrinkage of the upper boundary of TSH (from 5.5 to 2.5 ) as a diagnostic predictor of hypothyroidism might account for the surprising early reports of normal thyroid activity in depressed patients who had abnormal TRH tests, as well as those who responded to adjunctive T3. (2)

The report by Bunevicius and Prange that T3 had markedly different behavioral effects than T4 seems to have sunk beneath the conventional wisdom. (3)

The work by Maurice Preter and myself, via controlled contrasts of naloxone vs saline preceding lactate infusions in normal subjects, suggested persisting damage to the endogenous opioidergic system by early separation from parents. (4)  It cries out for independent critical replication.

Ned Shorter's conclusion that endocrine psychiatry is on the back-burner finds grim acknowledgement from NIMH program focus and grant support. Then again, almost everything clinical is on the back burner.




1. Stewart JW, Quitkin FM, McGrath PJ, Klein DF. Defining the boundaries of atypical depression: evidence from the HPA axis supports course of illness distinctions. J Affect Disord. 2005; 86(2-3): 161-7.

2. Baloch Z, Carayon P, Conte-Devolx B, et al.  Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease Thyroid 2000; 13 (1): 3–126.

3. Bunevicius R, Prange AJ. Mental improvement after replacement therapy with thyroxine plus triiodothyronine: relationship to cause of hypothyroidism. Int J Neuropsychopharmacol. 2000; 3(2 :167-74.

4. Preter M, Klein DF. Lifelong opioidergic vulnerability through early life separation: a recent extension of the false suffocation alarm theory of panic disorder. Neurosci Biobehav Rev.2014; 46(3: 345-51.


Donald F. Klein

April 9, 2015